Clinical Characteristics and Visual Outcomes in Infectious Scleritis: a Review Emeline Radhika Ramenaden George Washington University

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2013 Clinical characteristics and visual outcomes in infectious scleritis: A review Emeline Radhika Ramenaden George Washington University

Veena Rao Raiji George Washington University

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Recommended Citation Ramenaden, E.R., Raiji, V.R. (2013). Clinical characteristics and visual outcomes in infectious scleritis: A review. Clinical Ophthalmology, 7, 2113-2122.

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Open Access Full Text Article Review Clinical characteristics and visual outcomes in infectious scleritis: a review

Emeline Radhika Ramenaden Abstract: Infection is a very important but rare cause of scleritis, occurring in about 5%–10% Veena Rao Raiji of all patients presenting with scleral inflammation. However, due to the similarity of its presentation, infectious scleritis is often initially managed as autoimmune, potentially further Department of Ophthalmology, George Washington University, worsening its outcome. The overall visual outcome in infectious scleritis is generally worse Washington, DC, USA than its autoimmune counterparts, perhaps because of the delay in diagnosis or because of the aggressive nature of associated microbes. Thus, there is a definite need for insight into the diagnostic approach and treatment options for this ocular disease process. Several studies and case reports have been published in recent years that have provided useful information regarding the presenting clinical features and etiologic microbial agents in infectious scleritis. This review summarizes the important findings in the literature that may aid in differentiating infectious scleritis from other etiologies, including predisposing factors, microbe-specific characteristics, diagnostic tools, treatment modalities, and outcomes. Keywords: infectious scleritis, Pseudomonas, necrotizing scleritis, abscess

Background Scleritis is a state of ocular inflammation with a wide spectrum of clinical presentations and etiologic factors (Table 1). Specific etiologies of scleritis, varying from idiopathic to autoimmune to infectious, portend variable disease severity and outcome. Infection is an important but rare cause of the scleritis, occurring in about 5%–10% of all cases.1 However, due to the similarity of its presentation, infectious scleritis is often initially managed as autoimmune, potentially worsening its outcome. The overall visual outcome in infectious scleritis is generally worse than its autoimmune counterparts, perhaps because of this delay in diagnosis or because of the aggressive nature of associated microbes. Recent studies have identified specific inciting factors for infectious scleritis. Not surprisingly, these factors are typically surgery, most commonly pterygium surgery but also excisions of conjunctival neoplasms, cataract surgery, vitreoretinal surgeries, and glaucoma surgeries.2–4 Paula et al and Hodson et al report that the use of concomitant radiation or mitomycin C is also a risk factor.2,5 Trauma, especially with introduction of organic material to the ocular surface or self-inoculation from a distant site on the Correspondence: Emeline Radhika 6 Ramenaden body is also a significant inciting factor. In isolated cases, immunosuppression due to Department of Ophthalmology, human immunodeficiency virus or chemotherapy, may be a risk factor for spontane- George Washington University, ous cases of infectious scleritis.2,7,8 Interestingly, Meyer et al reported an individual 2150 Pennsylvania Ave, NW, Suite 2A, Washington, DC 20037, USA case of spontaneous infectious scleritis without any such prior history that revealed Tel +1 202 741 2800 Pseudomonas aeruginosa resistant to 4th generation fluoroquinolones, indicating the Fax +1 202 741 2805 Email [email protected] importance of considering infectious etiologies despite the lack of leading history.9 submit your manuscript | www.dovepress.com Clinical Ophthalmology 2013:7 2113–2122 2113 Dovepress © 2013 Ramenaden and Raiji. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/OPTH.S37809 permission from Dove Medical Press Ltd, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Ltd. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Ramenaden and Raiji Dovepress

Table 1 Types of scleritis Another known characteristic of infectious scleritis is Anterior-diffuse Greater than 50% contiguous scleral its sometimes delayed presentation, occurring months to involvement. Associated with systemic years after ocular surgery or trauma. Jain et al proposed that disease. Generally in women 40–70 years conjunctival and tear film alterations may expose underly- old or men 30–60 years old. Rare in the young and the very old. ing necrotic scleral collagen to microorganisms and allow Anterior-nodular Distinct nodules present. Associated with localization, adherence, colonization and invasion.1 Microbes isolated disease. Both sexes generally can then remain dormant within the sclera for years without involved, 40–60 years old. Anterior-necrotizing Scleral necrosis with scleromalacia. inciting an inflammatory response, making the diagnosis of (with inflammation) Associated with systemic disease. infectious scleritis in these cases quite difficult. It remains Generally in women in their 40s. unclear why these infections may be reactivated after such Anterior-necrotizing Scleral necrosis without scleromalacia. 12 (without inflammation) Usually associated with systemic disease. long periods of latency. Generally in women, 35–75 years old. According to one large retrospective study by Hodson Posterior scleritis Usually associated with anterior scleritis. et al, the median age of the patients at diagnosis of infec- Generally in women in their 60s. Diagnosis tious scleritis is 70 years old.2 Most studies reveal an older made using clinical and ultrasound findings. Infectious scleritis Generally necrotizing. Can have anterior population, suggesting that age may hold some significance and posterior involvement. Scleral ulcers in the diagnosis of infectious scleritis.2,13,14 Additionally, the with calcific plaque at the base and time from an identifiable inciting event to the presentation of microabscesses. Tissue extension beyond obvious clinical findings.* scleritis can range in 0 days up to 36 years, generally longer Notes: *Though infectious scleritis can present in many ways, these are the unique in postsurgical patients than the post-nonsurgical trauma clinical findings found most commonly in this review. Data from Raiji et al,45 and patients, with the longest latency period reported occurring Watson and Hayreh.46 after a history of pterygium surgery.2,10 While postoperative worsening of scleritis has been well In all cases of infectious scleritis, P. aeruginosa is the reported in those with preexisting autoimmune scleritis, a most common infectious agent.1,2 Additional identified concomitant infectious etiology is much less common. The microbes include Nocardia, Aspergillus, Fusarium, Candida, similarities in presentation between autoimmune and infec- Beauveria, Stenotrophomonas, Streptococcus, Staphylococ- tious scleritis often delays diagnosis. Infectious scleritis cus aureus (especially of the methicillin-resistant type), after pterygium surgery with adjunctive β-radiation and Serratia, Enterobacter, Achromobacter, Propionibacterium, mitomycin C has been well established.2,11,12 Several reasons Haemophilus, Alcaligenes, mycobacteria, and herpes viridae. may exist for this association. Meallet proposed in 2006 that In some cases, coinfections have been reported.2,15 Although the use of adjunctive therapies such as these are likely to com- P. aeruginosa as well as other bacterial and viral etiologies promise the integrity of episcleral conjunctival vessels and are most common in developed countries, fungi and Nocardia underlying tissue, thus inhibiting adequate wound healing and are relatively more prevalent in developing countries, perhaps leaving the sclera vulnerable to infection. He further hypoth- due to humid climates and increased exposure to soil.1 esizes that surgical techniques such as leaving bare sclera Retinal surgeries such as vitrectomy, scleral buckling exposed or excessive use of cautery, as well as poor contact lens with intrascleral fixation, and epiretinal membrane peel hygiene or nonhealing epithelial defects may all contribute.12 procedures have been associated with acid-fast organisms, P. aeruginosa, the most common agent in infectious scleritis, such as Mycobacterium chelonae, more so than anterior seg- utilizes neutrophil-activated collagenases to destroy tissue, ment procedures.2,16 These retinal surgeries have additionally especially when sclera is left bare. Other microbes have been associated with Pseudomonas, methicillin-resistant similar biochemical mechanisms by which they are able to Staphylococcus aureus, and coagulase-negative Staphylo- infiltrate ocular tissues.12 Furthermore, traditional antibiotic coccus albus.3,17 The use of sub-Tenon’s triamcinolone ace- regimens, both topical and systemic, remain inadequate due tonide injection has also been associated with the development to the avascularity of the sclera and the dense structure of of infectious scleritis in two cases, which were culture positive collagen fibers, limiting tissue penetration.12 Additionally, for Staphylococcus epidermidis and Nocardia.18,19 the misdiagnosis of infectious scleritis as a postoperative inflammatory complication leads to initial aggressive local Presentation and systemic corticosteroid therapy that further worsens their Infectious scleritis may present with certain clinical patterns infection and may lead to poor visual outcomes. that might facilitate more efficient diagnosis when recognized.

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Furthermore, because the prevalence of certain microbes in A black arc-shaped band from the initial ulcer site through infectious scleritis varies by environment, inciting event, or subsequent abscesses has been identified in some patients after sometimes even by symptomology, knowledge of this infor- resolution, indicating a track of disseminated infection.21 mation may allow faster microbial identification. Necrotizing scleritis tends to be the most common Similar to patients with autoimmune scleritis, patients presentation of infectious scleritis. A necrotizing pattern is with infectious scleritis commonly present with symptoms also seen in association with autoimmune scleritis with or of redness, pain, and epiphora.13 Infectious scleritis after without vasculitis or metabolic disorders, all of which require retinal surgery tends to be associated with more rapid and immunosuppression for treatment and would worsen visual extreme pain than anterior segment surgeries.3 The most outcome in infectious scleritis (Figure 4).1,15 Thus, infectious common clinical signs at presentation in a retrospective etiologies should be suspected in any case of progressive study of 55 patients with infectious scleritis included epis- indolent necrosis with suppuration, refractory to anti- cleral and conjunctival hyperemia (98%) and scleral necro- inflammatory regimens.1 Mild to moderate pain is generally sis (93%),2 noted consistently in other studies as well.1,12,13 associated with diffuse and nodular scleritis whereas severe In this large study, 19 eyes had isolated scleritis whereas pain is more frequently associated with necrotizing scleritis,24 37 involved adjacent ocular structures, including the cornea and extraocular muscles, both spreading primarily from the sclera to elsewhere or secondarily to the sclera.2 An anterior chamber reaction of greater than 1+ cell is usually present at the initial encounter.20,21 Endophthalmitis has also been documented as the presenting finding.1,11,13,22 Not surprisingly, retinal surgeries predisposed patients with infectious scleritis to posterior scleral thickening and retinal or choroidal detachments.3,16,17,21 More notably, patients with infectious scleritis may present with a scleral ulcer at sites of prior tissue penetration, at times including satellite abscesses or involving extraocular muscles, which may mimic orbital inflammatory syndrome.1,13,21 Calcified plaques are often found at the base of scleral ulcers (Figure 1).1,21 Unifocal or multifocal scleral abscesses are consistently reported, appearing as distinctly yellowish nodules under intact conjunctiva (Figure 2).1,13,23 Abscesses are characteristically scattered superiorly or infe- riorly along an arc of 3–4 mm from the limbus (Figure 3).21

Figure 1 Scleral ulcer with calcific plaque. Notes: (A) At presentation, there was a calcific plaque over the scleral ulcer bed (arrowhead). The ulcer progressed and became contiguous with a corneal infiltrate Figure 2 Slit lamp pictures depicting different clinical presentation. (arrow). (B) Multiple new nodules (arrowheads) from which P. aeruginosa was Notes: (A) Case no 2: multiple scleral abscess. (B) Case no 12: single scleral cultured, appeared on the 22nd day of hospitalization. ©1998 BMJ Publishing Group. abscess. (C) Case no 4: necrotic ulcer (post cataract surgery). (D) Case no 3: two Reproduced with permission from Hsiao CH, Chen JJ, Huang SC, Ma HK, et al. punched out ulcers. Reproduced with permission from Kumar SS, Das S, Sharma S Intrascleral dissemination of infectious scleritis following pterygium excision. Br J et al. Clinico-microbiological profile and treatment outcome of infectious scleritis: Ophthalmol. 1998;82(1):29–34.21 experience from a tertiary eye care eye center of India. Int K Inflam. 2012:753560.13

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found to be bacterial, with fewer cases being fungal.2,22 In developing countries, however, fungal etiologies are more common, likely related to differences in climate and environmental exposures.1,13 In general, fungal, nocardial and mycobacterial infections take longer to diagnose than bacterial infections.2 It is recommended that a complete diagnostic work-up of infectious etiologies include scleral scrapings and culture on blood and chocolate agar, brain–heart infusion broth, thioglycolate broth, nonnutrient agar with E. coli overlay, and Figure 3 Case 1: Scleral thinning from original ulcer through subsequent abscess Sabouraud dextrose agar.1 Diagnosis of viral etiologies like extended in an arc shape. Note: © 1998 BMJ Publishing Group. Reproduced with permission from Hsiao CH, herpes-related scleritis can be confirmed by scleral biopsy Chen JJ, Huang SC et al. Intrascleral dissemination of infectious scleritis following and the use of immunofluorescence, as well as positive titers pterygium excision. Br J Ophthalmol. 1998;82(1):29–34.21 or signs of chronic herpetic infection like corneal hypoes- suggesting that pain out of proportion to examination findings thesia.14,20 Kumar et al advocate scleral scrapings in every may be indicative of a possible infectious etiology. case of suspected infectious scleritis that does not respond Other ocular complications noted at the time of presenta- to initial antibiotics, not only for the purpose of diagnosis tion of infectious scleritis are decreased vision, peripheral but also to debulk necrotic tissue and improve antimicrobial keratitis presenting as interstitial keratitis or thinning with penetration.13 ulceration, or glaucoma.2,20 In addition to cues from clinical presentation, history, and For the purposes of this review, infectious agents that have slit-lamp examination, the use of ancillary testing has been not been shown in the literature to cause primary scleritis proposed to be of diagnostic value in infectious scleritis. were excluded. Nguyen and Yiu comment on the utility of ultrasound biomicroscopy in allowing early detection of scleritis-associated Diagnosis retinal and choroidal detachments.25 Ultrasound biomicros- In two large retrospective reviews done in the United States copy is further used to demonstrate anterior ciliary body rota- and Taiwan, the majority of cases of infectious scleritis were tion and elimination of the ciliary sulcus in infectious scleritis along with a diffuse lacy-appearing choroidal thickening.25 Additionally, they suggest that optical coherence tomography 2.00000 allows the visualization of small vitreoid opacities and abnor- mal subretinal deposits, which may represent lipofuscin-laden macrophages in infectious scleritis (Figure 5).25 Su et al performed a prospective study in which they found 1.00000 that elevated erythrocyte sedimentation rate and C-reactive protein were noted in 9 of 12 patients with infectious scleritis.10

BCVA (logMAR) While these general inflammatory parameters can be elevated in

0.00000 any case of inflammation, in these patients, both of these values returned to normal with treatment of the infection.10 Addition- ally, these patients underwent a thorough laboratory work-up to document the lack of any associated underlying autoimmune Before After Before After Before After Before After state that could have explained these laboratory findings.

Diffuse Nodular Infectious Noninfectious necrotizing necrotizing Microbe-specific findings Figure 4 Visual acuities before and after treatment. Notes: Patients with infectious necrotizing scleritis had the poorest BCVA before Bacterial etiologies comprise the majority of cases of infec- and after treatment. The data are presented as the mean ± standard deviation. tious scleritis.5 Bacterial proteins may contribute to tissue Reproduced with permission from Ahn SJ, Oh JY, Kim MK, Lee JH, Wee WR. Clinical features, predisposing factors, and treatment outcomes of scleritis in the damage via proteases and activation of tissue complement Korean population. Korean J Ophthalmol. 2010;24(6):331–335.15 pathways.5 Pseudomonas aeruginosa represents about 85% Abbreviations: BCVA, best corrected visual acuities; logMAR, logarithmic value of the minimal angle of resolution. of cases of bacterial scleritis.5 Thus, most findings discussed

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at the site of pterygium excision. This case responded well to topical ciprofloxacin and intravenous cephatholin as well as oral diclofenac.5 Altman et al discussed four cases of S. pneumoniae scleritis that were treated with intravenous and topical antibiotics, two of which had full resolution and good visual outcome and two that had more devastating outcomes. One of these latter patients developed endophthalmitis requiring enucleation and one developed scleral perforation requiring a corneoscleral graft with resulting count fingers visual outcome.11 Therefore, S. pneumoniae represents a potentially aggressive form of infectious scleritis. Stenotrophomonas maltophilia is a rare aerobic nonfer- mentative Gram-negative bacterium that is difficult to treat. Lin et al reported a case of S. maltophilia-associated infectious scleritis that occurred 18 years after pterygium surgery.28

Figure 5 Advanced imaging studies of complications of infectious scleritis. Ramos-Esteban and Jeng reported a case of S. maltophilia Notes: (A) 35 MHz immersion ultrasound biomicroscopy demonstrating shallow scleritis in which ultrasound biomicroscopy revealed a anterior chamber, thickened and anteriorly rotated ciliary body (arrow), and elimination of the ciliary sulcus. (B) Thickened episcleral, scleral, and choroidal dome-shaped mass over an area of a partial-thickness scleral tissues are evident in the magnified view. (C) 10 MHz B-scan ultrasonography laceration after minor ocular trauma.29 In one particular case, showing double retinal and choroidal detachment, L-12 view, (D) L-mac view, and (E) spectral optical coherence tomography showing vitreous clumps (dotted full resolution seemingly occurred after fortified topical and arrows and circles), subretinal fluid, and subretinal precipitates (solid arrow). Reproduced with permission from Nguyen P, Yiu SC. Imaging studies in a case of systemic antibiotics as well as surgical debridement and patch infectious scleritis after pterygium excision. Middle East Afr J Ophthalmol. 2012;19(3): grafting. Interestingly, however, 5 months after resolution, 337–339.25 Abbreviations: L-12, longitudinal-12 view; L-mac, longitudinal-macular view. this patient presented with intrascleral dissemination of the same infection, indicating the importance of long-term in relevant studies are largely in the context of Pseudomonas follow-up and the possibility of microinvasion greater than scleritis. Though these findings are generally shared by most clinically detectable.28 infectious etiologies, there are certain characteristics or out- Mycobacterium tuberculosis scleritis is rare. The myco- comes associated with microbes other than Pseudomonas bacteria itself can cause an immune-mediated inflammatory that may be indicative of other etiologies. microangiopathy and may indirectly lead to an inflamma- Staphylococcus aureus is also an established cause of tory scleritis.1 Kesen et al reported a case of a 54-year-old bacterial scleritis. As reported by Arora et al, S. aureus woman with 6 months of eye pain and nodular scleritis scleritis presented as a pyomyositis with an inverse hypopyon unresponsive to steroids and methotrexate. She was found and localized scleral thinning in a patient with a large thigh to be QuantiFERON® gold–positive with hilar granulomas abscess.26 Lee et al reported a case of methicillin-resistant on CT, but due to initial lack of response to quadruple S. aureus 6 months after pterygium excision that was initially tuberculosis therapy and a bronchoalveolar lavage negative misdiagnosed clinically as Pseudomonas and was unrespon- for acid fast bacilli, the regimen was abruptly discontinued sive to systemic amikacin and ceftazidime as well as topical and immunosuppression was restarted. She later presented ciprofloxacin. They suggest that MRSA should be suspected with scleral rupture and polymerase chain reaction of the when typical postoperative antibiotics are ineffective.27 specimen at that time revealed the M. tuberculosis genome.30 Streptococcus pneumoniae is a common infectious Mycobacterial infections other than tuberculosis (MOTT) agent in children and the elderly with concomitant joint, have a low incidence in humans but present in a disseminated cardiovascular, gastrointestinal, and genitourinary infections. form in immunocompromised patients. These microbes Recently, this bacteria has been associated with infectious are known to be difficult to isolate by common laboratory scleritis after pterygium surgery with concurrent use of techniques and are easily confused with other pathogens. β-irradiation or mitomycin C.5,11 Paula et al reported a case Therefore, they should be suspected in immunocompromised of S. pneumoniae scleritis that presented with mucopurulent patients with +AFB (acid-fast bacilli) or granulomatous discharge, vascular congestion, and three scleral abscesses noncaseating inflammation.31 M. chelonae is among these with necrosis and a small aqueous fistula in the upper sclera MOTT species and has been shown to cause scleritis.31 M.

Clinical Ophthalmology 2013:7 submit your manuscript | www.dovepress.com 2117 Dovepress Ramenaden and Raiji Dovepress chelonae is a quick-growth mycobacteria easily confused Herpetic scleritis has similar rates of increased intraocular with Nocardia or M. fortuitum that requires several tissue pressure when compared to idiopathic types.20 Interestingly, samples to adequately differentiate, thereby delaying diag- systemic symptoms are generally not present in patients with nosis and treatment. It is known to be resistant to typical herpetic scleritis, and the central cornea tends to be spared.14 antituberculous drugs. Treatment must be continued for 4 This lack of typical corneal findings in herpetic scleritis weeks to 6 months after full resolution of clinical signs, generally delays its diagnosis; therefore, a high index of sus- although due to the rarity of this diagnosis, the exact time picion should exist when the previously discussed symptoms of treatment has not yet been established.31 and signs are noted.20 Definitive diagnosis can be made by Lepromatous leprosy, another mycobacterium-related immunohistopathological analysis of scleral biopsies, clinical disease, has been reported to present with unilateral ocular evidence of dendritic or stromal keratitis, or positive anti-HSV involvement as interstitial keratitis and granulomatous ante- or anti-VZV titers.20 Herpetic scleritis typically responds rior uveitis. In one report by Poon et al, an initial response was quickly to acyclovir treatment, within 3–8 weeks,14,20 with achieved using antileprotics and anti-inflammatory agents; the inflammation generally lasting from 5–32 months.14 The however, the patient went on to develop recurrent episodes initial dosage of acyclovir used in these studies was 800 mg of scleritis that necessitated multiple scleral patch grafts five times daily,14,20 with most patients requiring a lower for scleral thinning, subsequently requiring enucleation. maintenance dose of acyclovir to prevent recurrence, which Histology failed to demonstrate lepromatous infection, but typically occurs at the same site as previous inflammation.14 showed chronic nongranulomatous scleritis.32 Previous treatment with immunosuppressive therapy can Toxoplasma gondii, an obligate intracellular parasitic prolong and worsen herpetic scleral inflammation.14 protozoan, is usually associated with posterior intraocular Fungal scleritis, unlike bacterial and viral scleritis, has inflammation; however, it has been reported by Schuman worse overall outcomes (Table 2).1,34 Jain et al report that et al to cause scleritis in five cases.33 Two of those patients fungal scleritis is more commonly encountered in hot, humid were diagnosed clinically and treated successfully with climates, generally following surgical or accidental trauma.1 medical therapy. Three of the patients, two of whom were In cases of fungal scleritis, full thickness corneal inflamma- immunosuppressed, went undiagnosed without treatment tion contiguous with scleral lesions is quite common.1 In for toxoplasmosis, and progressed to eventually require their study, patients with fungal scleritis progressed despite enucleation. Thus, T. gondii, while rare, should be suspected treatment, to develop rapidly progressive cataracts, serous in scleritis with associated retinochoroiditis, especially in retinal or choroidal detachments, phthisis, or endophthalmi- those who are immunosuppressed.33 tis, of which a majority progressed to evisceration.1 Although herpes infections of the eye, both HSV and VZV, Jain et al further report that Aspergillus and Nocardia have predominantly been thought of in relation to the cornea are the most common fungal agents in infectious scleritis.1 and ocular adnexa, they have also been reported in cases of Fincher and Fulcher recovered Aspergillus fungal hyphae infectious scleritis.14 Gonzalez-Gonzalez et al conducted a from a biopsy of a scleral nodule in one patient with a large retrospective study of patients with herpetic scleritis known history of intravenous drug abuse.35 This infection and found a predominance of middle-aged females with was successfully treated with intravenous caspofungin as unilateral findings and moderate to severe pain.20 The acuity of the presentation of herpes scleritis can be variable. Table 2 Comparison of fungal cases with other infectious 20 While one study reports acute onset, another reports scleritis cases chronic herpes-associated inflammation with an average of Fungal scleritis Others 3.2 years of symptoms prior to diagnosis.14 Herpetic scleritis Total number 8 13 is more likely to be of the diffuse anterior type than of the Associated corneal 3/8 (40%) 4/13 (30%) nodular or necrotizing type.20 Perilimbal devascularization infiltration with peripheral corneal thinning along with a significant Multifocal scleral abscess 3/8 (40%) 0 Endophthalmitis 3/8 (40%) 0 amount of associated uveitis are findings associated with Eviscerated 4/8 (50%) 0 herpetic scleritis, with significantly greater vision loss noted Useful vision 1/8 (13%) 6/13 (46%) in herpes than in idiopathic cases of scleritis.14 In general, (95% CI, 0%–36%) (95% CI, 19%–63%) herpes infections are not associated with posterior scleritis, Note: Microbial scleritis – experience from a developing country. © 2008 Nature Publishing Group. Reproduced with permission from: Jain V, Garg P, Sharma S. Microbial vitreoretinal involvement, or scleromalacia perforans.14,20 scleritis-experience from a developing country. Eye (Lond). 2009;23(2):255–261.1

2118 submit your manuscript | www.dovepress.com Clinical Ophthalmology 2013:7 Dovepress Dovepress Clinical characteristics and visual outcomes in infectious scleritis well as repeated surgical drainage of all emerging scleral overuse of cautery and adjunctive therapy during surgical abscesses.35 Nocardia is much more common in agricultural procedures may spare the episcleral blood flow and allow bet- societies, where exposure to soil or plant matter is prevalent, ter wound healing and resistance to infection.21 Most studies as compared with other infectious etiologies.1,34 Generally, advocate the avoidance of bare sclera techniques that leave Nocardia does not cause fulminant infection; however, in the ocular surface vulnerable to infection. However, in one the presence of immunosuppression such as oral steroids study by Tittler et al the use of amniotic membrane over an the presentation can be devastating, and can progress area of debridement was discouraged, suggesting that it pro- to ocular infection and even involve the central nervous vides maximum exposure for topical antibiotics and prevents system.36 In addition to the common findings in scleritis the incubated microbes from staying at the site, with adequate of ocular pain, redness, and blurred vision, patients with re-epithelialization occurring shortly after debridement.41 If Nocardia-related scleritis have nodular lesions that present a bare sclera technique is chosen, close follow-up should be as pointed abscesses.34 Nocardia should be suspected when undertaken with examination for scleral ischemia, the first scleral inflammation does not respond to intensive first-line sign of which should prompt conjunctival autografting or antibiotic therapy.36 Direct smear is usually unrevealing; other scleral reinforcement.21 diagnosis of Nocardia is more easily made with Gram stain One large study of patients with infectious scleritis by or acid-fast stain.34 One case of Nocardia scleritis showed Hodson et al employed various antimicrobial treatment full resolution with debridement and systemic trimethoprim/ regimens: 95% topical, 77% oral, and 11% intravitreal sulfamethoxazole,37 but it has also been shown to have very therapy. Despite a mean treatment duration of 50 days, good sensitivity to amikacin.36 medical therapy was adequate as the sole treatment in only Other rare fungi have been documented to cause scleritis. 18% of patients, with most requiring surgical debridement.2 Pseudallescheria boydii, a saprophytic fungus frequently A higher rate of enucleation or evisceration was present in isolated from agricultural soil and polluted water, has been those treated solely with medical methods.42 Cryotherapy, reported to present with extensive involvement of the pos- lamellar or penetrating corneoscleral grafts, or removal of terior sclera with abscesses.38 Paecilomyces lilacinus is an hardware in addition to intensive antibiotics improves overall environmental mold found in soil and vegetation that rarely outcomes in patients.2,43 Early and repetitive surgical debride- causes human infection. Chung et al discussed a case of ment is heavily advocated in multiple studies.1,13,22,41,42 Tittler P. lilacinus that presented as multiple scleral abscesses with et al showed a 100% globe preservation rate, best corrected fibrinoid anterior chamber reaction that then progressed vision of 20/120 to 20/400, fewer complications, and shorter to involve the cornea despite topical and oral antifungals. hospital stays with prompt surgical debridement at diagnosis Debridement and intracameral injection of amphotericin B (within 2.5 days).41 Most significantly, it has been shown in was required for resolution 4 months later, although it resulted multiple studies that the inflamed area is often found intra- in phthisis and light perception vision.39 Lastly, Scedosporium operatively to be much larger than clinically judged by slit prolificans, an emerging opportunistic fungus, was found lamp exam (Figure 6).1,13,21,22 Furthermore, there is sometimes to cause late-onset scleritis with a median presentation of a notable tunnel lesion of scleral ulcer and small pockets 7.6 years after pterygium excision. Jhanji et al reported that of abscess within necrotic sclera that require very careful voriconazole is the most effective medical therapy for S. exploration. Some patients require a scleral patch graft due prolificans scleritis, although it only allowed resolution in six to the large area of resulting debridement.1,13 of nine cases.40 Thus, it is evident that overall visual prog- The use of a fascia lata grafts in combination with an amni- nosis in fungal scleritis is generally poor, possibly because otic membrane graft after surgical debridement for infectious of delayed diagnosis, poor penetration of antifungals into scleritis was used successfully by Zheng et al in two patients, avascular sclera, nonavailability of fungicidal agents, or the one with Pseudomonas and one with fungal scleritis. Fascia ability of organisms to persist in avascular scleral tissue for lata was thought to be ideal because of its bioadaptability in long periods of time without inciting inflammatory response, size and thickness as well as its good cosmetic appearance. allowing progressive worsening.1 Prior to grafting, necrotic scleral tissue was removed and the surface was irrigated with ceftazidime. The fascia lata was Treatment then dissected from the biceps femoris in the leg and placed It has been suggested repeatedly that prevention of infectious over the defect with an overlying amniotic membrane or scleritis is most important for patient outcome. Avoiding pedicle conjunctival flap, with subconjunctival injection of

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systemic absorption of this continuous antibiotic regimen was not adequately addressed.12

Outcomes As may be expected after the discussion in this review, infectious scleritis has worse visual acuity after remission and longer resolution time as compared to noninfectious scleritis.15 Not surprisingly, isolated infectious scleritis has better prognosis than sclerokeratitis. Hodson et al reported that 50% of eyes in their study with infectious scleritis lost functional vision, indicating best corrected Snellen visual acuity less than 20/200.2 Poor prognostic indicators in infectious scleritis include a presenting vision worse than 20/200 or concomitant keratitis Figure 6 Scleral ulcer before and after debridement Notes: (A) The scleral ulceration located at the 9 o’clock position. Severe congestion or endophthalmitis, which tend to require enucleation or and subconjunctival abscess were noted at 10 o’clock position under the biomicroscope. 2 (B) After the surgical debridement, the scleral wound was left open. in comparison evisceration more commonly. Additionally, fungal etiologies with (A), the involved area was more extensive. (C) Ten days later, the debrided area tend to have worse prognosis, likely secondary to delays in was healing. © 1997 BMJ Publishing Group. Reproduced with permission from: Lin CP, 15 Shih MH, Tsai MC. Clinical experiences of infectious scleral ulceration: a complication diagnosis. However, there is no difference in duration of of pterygium operation. Br J Ophthalmol. 1997;81(11):980–983.22 treatment or need for surgical debridement when comparing bacterial versus fungal cases.2 The degree of final vision loss ceftazidime followed by oral cefdinir for 4 days. This was the does not significantly correlate with any specific inciting only group to report the use of both a fascia lata and amni- factor, infectious organism, nor the amount of time from otic membrane grafts, and both patients showed evidence of symptom initiation to diagnosis. Rather, visual outcome only resolution.44 significantly correlates with low presenting vision.2 Not unlike fascia lata grafts, tectonic scleral reinforce- Hodson et al report that the median time between comment with preserved pericardium and donor corneal tissue mencing treatment and resolution of scleritis was 46 days was used successfully in a patient with nocardial scleritis with 50% of eyes losing functional vision.2 Only one case of that progressed to scleral perforation and uveal prolapse. recurrence was noted after cessation of treatment in this study This technique along with topical and oral antibiotics after apparent full resolution.2 Though recurrences are noted allowed salvaging of the eye and a final Snellen visual commonly as new nodules or necrotic areas during active acuity of 20/70.36 infectious scleritis, the appearance of such recurrences after A variety of medical modalities have been suggested as achieving full resolution of scleritis is generally rare.2,41 good adjunctive treatments to surgical debridement. These Surgical debridement repeatedly resulted in much greater include systemic and topical antibiotics, subconjunctival overall improvement in outcome. Sahu et al showed an improve- injections of antibiotic at both ends of the scleral lesion, and ment in vision of greater than two lines in 60% of patients with wound irrigation with antibiotic solution one to two times a use of concurrent debridements as needed.13 Reversible causes day followed by normal saline after improvement.22 Intraocular of vision loss include cataract, fibrotic pupillary membranes, antibiotics should be used in all cases of endophthalmitis, and repairable retinal detachments, and corneal opacities. Irrevers- topical steroids should always be initiated only when antibiot- ible causes include chronic retinal and choroidal detachments, ics have been reliably used for several days.13 glaucoma, or the need for enucleation or evisceration.2,13 Finally, Meallet proposed the use of continuous subpalpebral lavage antibiotics for the treatment of infectious Conclusion scleritis, reporting resolution of all six cases of scleritis in Infectious scleritis, though rare, is an important and immi- this study after this treatment.12 However, this technique was nently vision-threatening cause of scleritis. Therefore, it complicated by hyphema and cataract formation as well as is critical for eye care professionals to maintain infectious corneal thinning or dense corneal scar requiring corneal etiologies in their differential diagnosis for all patients transplants, indicating that important adjustments have yet with presenting symptoms of scleral hyperemia and sig- to be made to this technique. Additionally, the question of nificant ocular pain. Of particular interest are patients with

2120 submit your manuscript | www.dovepress.com Clinical Ophthalmology 2013:7 Dovepress Dovepress Clinical characteristics and visual outcomes in infectious scleritis a history of ocular surgery or trauma, regardless of how 4. Cunningham MA, Alexander JK, Matoba AY, Jones DB, Wilhemus KR. Management and outcome of microbial anterior scleritis. Cornea. remote the event, as infections appear to remain dormant 2011;30(9):1020–1023. within the sclera for months to years before reactivation. 5. Paula JS, Simão ML, Rocha EM, Romão E, Velasco Cruz AA. Atypical In addition, patients’ refractory to treatment for presumed pneumococcal scleritis after pterygium excision: case report and literature review. Cornea. 2006;25(1):115–117. autoimmune scleritis should be promptly considered for 6. Maskin SL. Infectious scleritis after a diabetic foot ulcer. Am J infectious etiologies, as their immunosuppressive therapy Ophthalmol. 1993;115(2):254–255. 7. Hwang YS, Chen YF, Lai CC, Chen HS, Hsiao CH. Infectious scleri- will inevitably worsen their infection. Scleral abscesses and tis after use of immunomodulators. Arch Ophthalmol. 2002;120(8): necrosis are common initial signs in infectious scleritis, 1093–1094. though many patients will present with more advanced 8. Moreno Honrado M, del Campo Z, Buil JA. A case of necrotizing scleritis resulting from Pseudomonas aeruginosa. Cornea. 2009;28(9): sequelae such as retinal or choroidal detachments and 1065–1066. glaucoma. Bacterial, viral, and fungal etiologies exist for 9. Meyer JJ, Espandar L, Marx DP, Vitale A, Moshirfar M. Pseudomonas scleritis resistant to fourth-generation fluoroquinolones in a patient infectious scleritis, with Pseudomonas aeruginosa being without prior trauma or surgery. Ocul Immunol Inflamm. 2008;16(3): the most common overall cause and fungi having the worst 127–129. overall prognosis. Appropriate diagnosis generally requires 10. Su CY, Tsai JJ, Chang YC, Lin CP. Immunologic and clinical manifestations of infectious scleritis after pterygium excision. scleral scrapings with thorough culturing and immunohis- Cornea. 2006;25(6):663–666. tochemical staining. However, empiric treatment may be 11. Altman AJ, Cohen EJ, Berger ST, Mondino BJ. Scleritis and Streptococcus pneumoniae. Cornea. 1991;10(4):341–345. necessary when these laboratory tests return inconclusive. 12. Meallet MA. Subpalpebral lavage antibiotic treatment for severe The characteristics of presentation for specific microbes infectious scleritis and keratitis. Cornea. 2006;25(2):159–163. discussed in this review, along with ancillary tests such 13. Kumar Sahu S, Das S, Sharma S, Sahu K. Clinico-microbiological profile and treatment outcome of infectious scleritis: experience from as ultrasound and optical coherence tomography, may a tertiary eye care center of India. Int J Inflam. 2012;2012:753560. facilitate appropriate diagnosis and therapy in these 14. 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Necrotizing scleritis after ocular surgery. involved sclera is consistently larger intraoperatively than Trans Ophthalmol Soc U K. 1979;99(1):146–149. is initially judged on clinical exam, further supporting 18. Gharaee H, Khalife M, Poor SS, Abrishami M. Infectious scleritis after subtenon triamcinolone acetonide injection. Ocul Immunol Inflamm. the importance of surgical exploration. About half of all 2011;19(4):284–285. patients with infectious scleritis maintain functional vision 19. Seth RK, Gaudio PA. Nocardia asteroides necrotizing scleritis associated with subtenon triamcinolone acetonide injection. Ocul after resolution. Recurrences rarely occur, but highlight the Immunol Inflamm. 2008;16(4):139–140. importance of continued close observation for an extended 20. Gonzalez-Gonzalez LA, Molina-Prat N, Doctor P, Tauber J, Sainz de period of time even after clinical resolution in patients with la Maza MT, Foster CS. 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